The compounds of the present invention are useful in the treatment of diseases or pathological conditions in which endothelial dysfunction is known to be a pathogenic and/or aggravating mechanism. Such pathologies are: atherosclerosis, the existence of vascular risk factors (dyslipidaemia, diabetes, systemic arterial hypertension), the various clinical forms of myocardial or peripheral ischaemia, cardiac insufficiency and the various forms of pulmonary arterial hypertension. The said compounds are also useful in the treatment of patients undergoing heart transplantation or vascular repermeabilisation, such as a bypass, thrombolysis or arterial dilatation with or without a stent.
A reduction in the vascular availability of nitrogen monoxide (NO) constitutes the major mechanism of endothelial dysfunction observed in the diseases and pathological conditions mentioned above and explains its pathogenic role (Cardiovasc. Res., 1999, 43, 572; Coronary. Art. Dis. 1999, 10 277; Coronary. Art. Dis., 1999, 10, 301; Coronary. Art. Dis., 1999, 10, 287; Coronary. Art. Dis., 1999, 10, 295).
In the said pathological conditions, the endothelial dysfunction may in fact result from two main mechanisms: 1) inadequate production of NO associated with inhibition of endothelial NO synthase by endogenous inhibitors, such as ADMA (asymmetric dimethyl-arginine), the plasma concentration of which increases in patients exhibiting cardiovascular risk factors (Cardiovasc. Res., 1999, 43, 542; Hypertension, 1997, 29, 242; Circulation, 1997, 95, 2068), 2) inactivation of the NO by the superoxide anion (O2xe2x88x92), the production of which is increased in pathological conditions (Cardiovasc. Res., 1999, 43, 562; Eur.J Biochem. 1997, 245, 541; J. Clin. Invest., 1993, 91 2546).
Under normal conditions, NO produces major effects such as: 1) regulation of arterial vasomotricity by means of its vasodilator effect (N Engl. J Med., 1993, 329, 2002; Nature, 1980, 288, 373), 2) limitation of platelet adhesion and aggregation (Trends Pharmacol. Sci., 1991, 12, 87), 3) control of the adhesion of leukocytes and monocytes to endothelial cells (Proc. Natl Acad. Sci. USA, 1991, 88, 4651), 4) inhibition of the proliferation of vascular smooth muscle cells (Cardiovasc. Res., 1999, 43, 580, Circulation, 1993, 87 V51), which explains why the deficiency of NO in the arterial wall is favourable to pathological phenomena, such as vasoconstriction, thrombosis, lipid accumulation and proliferation of vascular smooth muscle cells.
In vitro experiments have enabled it to be shown that the compounds of the present invention are capable of limiting the endothelial dysfunction and reduced vascular availability of NO that were induced by tests involving the two physiopathological mechanisms already mentioned: inhibition of endothelial NO synthase and oxidative stress due to production of O2xe2x88x92.
Besides the fact that they are new, the compounds of the present invention, by virtue of their specific pharmacological activity, which is capable of limiting the development of endothelial dysfunction, are useful in preventing the development, extension and complications of atherosclerotic lesions, especially in patients exhibiting a vascular risk factor (dyslipidaemia, diabetes, arterial hypertension), and in treating the various clinical forms of myocardial or peripheral ischaemia, cardiac insufficiency and the various forms of pulmonary arterial hypertension. The compounds are also used for preventing vascular complications (spasm, thrombosis, restenosis, accelerated atherosclerosis) in patients undergoing a bypass, vascular dilatation with or without a stent or other forms of vascular repermeabilisation and also heart transplantation.
More specifically, the present invention relates to compounds of formula (I): 
wherein:
X represents:
a monocyclic or bicyclic, saturated, partially unsaturated or aromatic heterocycle, having from 5 to 12 ring members, containing from 1 to 3 hetero atoms selected from oxygen, nitrogen and sulphur but containing at least one nitrogen atom, said heterocycle being bonded to the remainder of the molecule by said nitrogen atom, and said heterocycle being optionally substituted,
or a group of formula xe2x80x94NR2R3 wherein R2 represents a hydrogen atom or a linear or branched (C1-C6)alkyl group, and R3 represents an aryl group optionally substituted, a 1,3-dihydro-2H-benzimidazolyl-2-one group, or a linear or branched (C1-C6)alkyl group substituted by a monocyclic or bicyclic, saturated, partially unsaturated or aromatic heterocycle, having from 5 to 12 ring members, containing from 1 to 3 hetero atoms selected from oxygen, nitrogen and sulphur but containing at least one nitrogen atom, said heterocycle being optionally substituted,
n in represents zero or 1,
R1 represents a hydrogen atom or a linear or branched (C1-C6)alkyl group,
Ra represents a single bond or a linear or branched (C1-C6)alkylene chain,
A represents a nitrogen atom or a CH group, but A represents only a CH group when Ra represents a single bond, and A represents only a nitrogen atom when n represents zero,
E represents a nitrogen atom or a CRe group wherein Re represents either a hydrogen atom, or a bond to a carbon atom of W, it being understood that at least one of the groups A and E represents a nitrogen atom,
Rb represents a single bond or a linear or branched (C1-C6)alkylene chain, one of the carbon atoms of which is optionally replaced by an oxygen atom or a sulphur atom,
W represents an aryl or heteroaryl group, each of those groups being optionally substituted,
their optical isomers, their hydrates, their solvates and addition salts thereof with a pharmaceutically acceptable acid, it being understood that:
xe2x80x9caryl groupxe2x80x9d is understood to mean a group selected from phenyl, biphenyl, bicyclo[4.2.0]octa-1,3,5-trienyl, naphthyl, dihydronaphthyl, tetrahydronaphthyl, indanyl and indenyl,
xe2x80x9cheteroaryl groupxe2x80x9d is understood to mean an aryl group as defined above containing from 1 to 3 identical or different hetero atoms selected from oxygen, nitrogen and sulphur,
xe2x80x9coptionally substitutedxe2x80x9d, when associated with xe2x80x9cheterocyclexe2x80x9d, xe2x80x9caryl groupxe2x80x9d or xe2x80x9cheteroaryl groupxe2x80x9d, is understood to mean optionally substituted by one or more identical or different groups selected from halogen, linear or branched (C1-C6)alkyl, hydroxy, linear or branched (C1-C6)alkoxy, mercapto, linear or branched (C1-C6)alkylthio, linear or branched (C1-C6)trihaloalkyl, cyano, nitro, amino, linear or branched (C1-C6)-alkylamino, dialkylamino in which each alkyl moiety has from 1 to 6 carbon atoms and is linear or branched, and methylenedioxy,
xe2x80x9coptical isomersxe2x80x9d are understood to mean the enantiomers and diastereoisomers.
Among the pharmaceutically acceptable acids, there may be mentioned by way of non-limiting example hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, acetic acid, trifluoroacetic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, tartaric acid, maleic acid, citric acid, ascorbic acid, oxalic acid, methanesulphonic acid, camphoric acid.
The compounds of the invention are preferably the compounds of formula (IA): 
wherein X, R1, Ra, A, E, Rb and W are as defined for formula (I).
According to an advantageous embodiment of the invention, the preferred compounds are the compounds of formula (I) wherein X represents a heterocycle as defined for formula (I).
According to another advantageous embodiment, the preferred compounds of the invention are the compounds of formula (I) wherein X represents a group of formula xe2x80x94NR2R3 as defined for formula (I).
Especially advantageously, the preferred compounds of the invention are the compounds of formula (I) wherein X represents a 1-indolinyl or 2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-1-yl group, each of those groups being optionally substituted by one or more groups as defined for formula (I).
Also especially advantageously, the preferred compounds of the invention are the compounds of formula (I) wherein X represents a group of formula xe2x80x94NR2R3 wherein R2 represents a hydrogen atom and R3 represents an optionally substituted phenyl group.
According to an embodiment of the invention of interest, the preferred compounds of the invention are the compounds of formula (I) wherein W represents a heteroaryl group, and advantageously W represents a benzofuryl or indolyl group.
According to another embodiment of the invention of interest, the preferred compounds of the invention are the compounds of formula (I) wherein xe2x80x94Rbxe2x80x94W together form an aryloxyalkyl group in which the alkyl moiety has from 1 to 5 carbon atoms and is linear or branched and the aryl moiety is optionally substituted.
The preferred compounds of the invention are:
3-anilino-4-({2-[4-(phenoxymethyl)-1-piperidinyl]ethyl}amino)-3-cyclobutene-1,2-dione and its methanesulphonate,
3-(4-chloroanilino)-4-({2-[4-(phenoxymethyl)-1-piperidinyl]ethyl}amino)-3cyclobutene-1,2-dione and its methanesulphonate,
3-(2,3-dihydro-1H-indol-1-yl)-4-({2-[4-(phenoxymethyl)-1-piperidinyl]ethyl}amino)-3-cyclobutene-1,2-dione and its methanesulphonate,
3-({1-[2-(1-benzofuran-3-yl)ethyl]-4-piperidinyl}amino)-4-(4-fluoroanilino)-3-cyclobutene-1,2-dione and its methanesulphonate,
4-{[2-({1-[2-(1-benzofuran-3-yl)ethyl]-4-piperidinyl}amino)-3,4-dioxo-1-cyclobutene-1-yl]amino}benzonitrile and its methanesulphonate,
3-[(2-{4-[2-(4-fluorophenoxy)ethyl]-1-piperidinyl}ethyl)amino]-4-[(2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)amino]-3-cyclobutene-1,2-dione and its methanesulphonate
3-(5-methoxy-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-1-yl)-4-({2-[4-(phenoxymethyl)-1-piperidinyl]ethyl}amino)-3-cyclobutene-1,2-dione and its dihydrochloride,
3-[(2-{4-[2-(4-fluorophenoxy)ethyl]-1-piperidinyl}ethyl)amino]-4-(5-methoxy-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-1-yl)-3-cyclobutene-1,2-dione and its dihydrochloride
3-[(2-{4-[2-(4-fluorophenoxy)ethyl]-1-piperidinyl}ethyl)amino]-4-(4,5,6-trimethoxy-2,3-dihydro-1H-indol-1-yl)-3-cyclobutene-1,2-dione and its methanesulphonate,
3-(6-chloro-2,3-dihydro-1H-indol-1-yl)-4-[(2-{4-[2-(4-fluorophenoxy)-ethyl]-1-piperidinyl}ethyl)amino]-3-cyclobutene-1,2-dione and its methanesulphonate,
3-(2,3-dihydro-1H-indol-1-yl)-4-[({1-[2-(1H-indol-3-yl)ethyl]-3-piperidinyl}methyl)amino]-3-cyclobutene-1,2-dione and its hydrochloride,
3-(5,6-dimethoxy-2,3-dihydro-1H-indol-1-yl)-4-[(2-{4-[2-(4-fluoro-phenoxy)ethyl]1-piperidinyl}ethyl)amino]-3-cyclobutene-1,2-dione and its methanesulphonate,
3-[(2-{4-[2-(4-fluorophenoxy)ethyl]-1-piperidinyl}ethyl)amino]-4-(6-methoxy-2,3-dihydro-1H-indol-1-yl)-3-cyclobutene-1,2-dione and its methanesulphonate, and
3-(4,5-dimethoxy-2,3-dihydro-1H-indol-1-yl)-4-[(2-{4-[2-(4-fluoro-phenoxy)ethyl]-1-piperidinyl}ethyl)amino]-3-cyclobutene-1,2-dione and its methanesulphonate.
The isomers, hydrates, solvates and addition salts with a pharmaceutically acceptable acid of the preferred compounds of the invention form an integral part of the invention.
The present invention relates also to a process for the preparation of compounds of formula(I), characterised in that there is used as starting material a compound of formula (II): 
wherein G represents a linear or branched (C1-C4)alkyl group,
which compound of formula (II) is reacted with an amine of formula (III):
Xxe2x80x94Hxe2x80x83xe2x80x83(III)
wherein X is as defined for formula (I),
to yield a compound of formula (IV): 
wherein X and G are as defined hereinbefore,
which compound of formula (IV) is treated with a compound of formula (V): 
wherein n, R1, Ra, Rb, A, E and W are as defined for formula (I),
to yield compounds of formula (I) as defined: 
which compounds of formula (I) are purified, if necessary, according to a conventional purification technique, may, if desired, be separated into their different isomers according to a conventional separation technique, and are converted, if desired, into addition salts thereof with a pharmaceutically acceptable acid.
The compounds of formulae (II), (III) and (V) are either commercial products or are obtained according to conventional methods of organic synthesis.
The compounds of the present invention are useful in the treatment of diseases or pathological conditions in which endothelial dysfunction is known. Accordingly, by virtue of their specific pharmacological activity the compounds of the invention are useful in preventing the development, extension and complications of atherosclerotic lesions, in the treatment of myocardial or peripheral ischaemia, cardiac insufficiency, pulmonary arterial hypertension, and in the prevention of vascular complications after vascular bypass, vascular dilatation, vascular repermeabilisation and heart transplantation.
The present invention relates also to pharmaceutical compositions comprising as active ingredient at least one compound of formula (I), an optical isomer, hydrate or solvate or an addition salt thereof with a pharmaceutically acceptable acid, in combination with one or more inert, non-toxic, pharmaceutically acceptable excipients or carriers.
Among the pharmaceutical compositions according to the invention, there may be mentioned more especially those that are suitable for oral, parenteral (intravenous, intramuscular or subcutaneous), per- or trans-cutaneous, nasal, rectal, perlingual, ocular or respiratory administration, and especially tablets or dragxc3xa9es, sublingual tablets, soft gelatin capsules, hard gelatin capsules, suppositories, creams, ointments, dermal gels, injectable or drinkable preparations, aerosols, eye or nose drops.
The useful dosage varies according to the age and weight of the patient, the route of administration, the nature and severity of the disorder, and whether any associated treatments are being taken, and ranges from 1 mg to 200 mg per day in one or more administrations.
The following Examples illustrate the invention but do not limit it in any way. The starting materials used are known products or are prepared according to known procedures. The various preparations yield synthesis intermediates for use in the preparation of the compounds of the invention.
The structures of the compounds described in the Examples were determined according to the usual spectrophotometric techniques (infrared, nuclear magnetic resonance, mass spectrometry, etc.).
The melting points were determined using a Kofler hotplate (K.) or a hotplate under a microscope (M.K.).